Soluble lymphotoxin is an important effector molecule in GVHD and GVL

Tumor necrosis factor (TNF) is a key cytokine in the effector phase of graftversus- host disease (GVHD) after bone marrow transplantation, and TNF inhibitors have shown efficacy in clinical and experimental GVHD. TNF signals through the TNF receptors (TNFR), which also bind soluble lymphotoxin (LT3), a TNF family member with a previously unexamined role in GVHD pathogenesis.We have used preclinical models to investigate the role of LT in GVHD.We confirm that grafts deficient in LT have an attenuated capacity to induce GVHD equal to that seen when grafts lack TNF. This is not associated with other defects in cytokine production or T-cell function, suggesting that LT3 exerts its pathogenic activity directly via TNFR signaling. We confirm that donor-derived LT is required for graft-versus-leukemia (GVL) effects, with equal impairment in leukemic clearance seen in recipients of LT- and TNFdeficient grafts. Further impairment in tumor clearance was seen using Tnf/ Lta/ donors, suggesting that these molecules play nonredundant roles in GVL. Importantly, donor TNF/LT were only required for GVL where the recipient leukemia was susceptible to apoptosis via p55 TNFR signaling. These data suggest that antagonists neutralizing both TNF and LT3 may be effective for treatment of GVHD, particularly if residual leukemia lacks the p55 TNFR.